The cause of sickle cell disease (SCD), the most common mutation in the beta-globin gene, is the substitution of valine for glutamic acid at the sixth residue of the beta chain. The incidence of the disorder among African-Americans is approximately 1 in 5000 births, with about 8% of African Americans being heterozygous for Hb S. Since SCD is a significant cause of morbidity and mortality, we propose to adapt silicon semiconductor processing techniques including photolithography, wet chemical etching and anodic bonding, to develop accurate, automated and cost-effective microdevices capable of direct detection of normal and/or betaS-globin alleles for clinically-significant sickling hemoglobinopathies. The resulting miniaturized DNA chip will perform sample preparation, nucleic acid amplification and miniaturized capillary electrophoresis (CE) or mutation detection by hybridization (MDBH) with high speed and throughput capabilities for DNA fragment sizing and mutation detection in the beta-globin gene. Related to this goal, the application aims to investigate the feasibility the a non-invasive method of prenatal diagnosis by analysis of fetal trophoblast cells. Using maternal peripheral blood collected during the first trimester, fetal trophoblast cells will be identified and isolated by means of different sized silicon filters etched in silicon chips. Beads containing monoclonal antibodies of unique specificity and high affinity against trophoblast membrane proteins will be employed, if necessary to achieve an additional level of cell separation. Although the yield of such cells is low, a sufficient number can be isolated to allow amplification by PCR, thus enabling identification of the sickle cell gene and ultimately allowing widespread non-invasive prenatal screening. Direct DNA amplification will then be performed following modification of the microfiltration chip and a fraction of the amplicons will be finally tested on an oligo-arrayed chip which incorporates overlapping segments of the whole beta-globin gene. It is anticipated that this technology will improve the speed, reliability, and accessibility of base recognition for rapid diagnosis of beta-globin gene mutations in compound heterozygotes for variants of SCD. Finally, implementation of the semiconductor chip manufacture technology will reduce contamination, consumption of sample and reagents, increase throughput and allow automated operation and integrated data acquisition and analysis of patients.